The Intramural Research Program is the ideal environment to undertake a project of this magnitude. The Laboratory of Neurogenetics has demonstrated expertise in handling large genomic datasets and has an exemplary track record of gene discovery. It is also remarkably cost effective to undertake this project within the Intramural Research Program. This project will place the Intramural Research Program at the forefront of dementia research and will greatly accelerate the pace of genetic discovery within the field. Specific Aim 1: We will perform genome sequencing of 3,000 LBD cases, 3,000 FTD cases and 2,500 neurologically normal control subjects. The Uniformed Services University will perform the sequencing using the Illumina X10 Sequencing platform. Specific Aim 2: We will analyze the genome sequence data generated from specific aim 1. The purpose of these analyses is to identify genetic loci that alter risk of developing disease and age at disease onset (i.e. genetic modifiers of phenotype). Specific Aim 3: We will make the genome sequence data generated from specific aim 1 publicly available. No embargo will be placed on access to the genome sequence data. These data will be the cornerstone of a new online resource that researchers can access, analyze, and combine with their own data to increase their power to detect new genetic loci. In this way, this unique database will be augmented over time and will greatly accelerate the pace of genetic discovery within the field. Our genome sequencing project is consistent with the strategic goals of the NIA. It aims to understand the dynamics of the aging process by unraveling the complex biology of dementia (Goal A). Unraveling the biology underlying dementia will improve the health, well-being and independence of adults as they age by improving our understanding of the aging brain, Alzheimer's disease, and other neurodegenerative disease (Goal D). We also hope that learning the genetics underlying dementia will provide therapeutic targets for drug discovery and ultimately lead to the development of effective interventions (Goal C). The intent of this project is to establish a public resource that will accelerate high quality research within the field, and that will grow over time (Goal G and H).